Expanded Clinical Spectrum Associated with Heterozygous Variants of RNU4ATAC

Introduction RNU4ATAC-opathies are characterized by biallelic pathogenic variants and include three recognized phenotypes: autosomal recessive Roifman syndrome, microcephalic osteodysplastic primordial dwarfism (MOPD), and Lowry-Wood syndrome. These disorders exhibit overlapping features such as microcephaly, developmental delay, skeletal dysplasia, and immunodeficiency. We report two cases of heterozygous pathogenic RNU4ATAC variants with similar manifestations, distinct from classic RNU4ATAC-opathy presentations. Case One A 17-year-old male presented with severe persistent asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Laboratory workup revealed low IgG level (454 mg/dL), normal IgA and IgM, and non-protective titers to tetanus and pneumococcal vaccines. Genetic testing revealed a heterozygous pathogenic RNU4ATAC n.13C>T variant. Cystic fibrosis (CF) and primary ciliary dyskinesia workup were negative. The patient was started on dupilumab 300 mg every 2 weeks for severe asthma and CRSwNP and subcutaneous immunoglobulin therapy (SCIG) for immunodeficiency with significant clinical improvement. Case Two A 23-three-year-old male presented with severe persistent asthma, CRSwNP, bronchiectasis, recurrent bacterial and viral upper and lower respiratory tract infections since childhood, allergic rhinitis, and myofibrillar myopathy. Immune evaluation was significant for absent antibody titers to measles, varicella, and pneumococcal vaccines with normal immunoglobulin and lymphocyte phenotype. CFTR gene sequencing revealed R75Q and 7T/7T variant consistent with atypical CF. Family history was notable for a brother with atypical CF and a sister with asthma. Primary immunodeficiency diseases (PIDD) genetics revealed two heterozygous pathogenic variants: RNU4ATAC n.40C>T and PMM2 c.368G>A (p. Arg123Gln). The patient was started on dupilumab for asthma and CRSwNP and SCIG for recurrent infections with marked improvement in his symptoms. Conclusion These cases expand the phenotypic spectrum associated with heterozygous RNU4ATAC variants, diverging from classical autosomal recessive RNU4ATAC-opathies. Our patients predominantly presented with severe asthma and CRSwNP, atypical for RNU4ATAC-associated disorders. Notably, there are reported associations of asthma and CRSwNP with 2q14.2 polymorphisms, where the RNU4ATAC gene is located. Coexisting atypical CF in one patient underscores the phenotypic complexity of these presentations and suggests that heterozygous RNU4ATAC variants may predispose to multisystem respiratory and immunologic dysfunction. These findings warrant consideration of extended genetic testing, including CFTR analysis, in patients with severe overlapping respiratory phenotypes.